Multifunctional Injectable Hydrogel Microparticles Loaded with miR‐29a Abundant BMSCs Derived Exosomes Enhanced Bone Regeneration by Regulating Osteogenesis and Angiogenesis

Abstract The study investigated whether both the osteogenic and angiogenic potential of Exos (Exosomes) can be enhanced by overexpression of exosomal miRNA (microRNA) and to confirm whether Exos loaded in HMPs (Hydrogel microparticles) exert long‐term effects during new bone formation. BMSCs and Exos are successfully obtained. In vitro and in vivo experiments confirmed that HDAC4 (Histone deacetylase 4) is inhibited by miR‐29a overexpression accompanied by the upregulation of RUNX2 (Runt‐related transcription factor 2) and VEGF (Vascular Endothelial Growth Factor), thereby enhancing osteogenic and angiogenic capabilities. The HMP@Exo system is synthesized from HB‐PEGDA (Hyperbranched Poly Ethylene Glycol Diacrylate)‐ and SH‐HA (Sulfhydryl‐Modified Hyaluronic Acid)‐containing Exos using a microfluidic technique. The HMP surface is modified with RGD (Arg‐Gly‐Asp) peptides to enhance cell adhesion. The system demonstrated good injectability, remarkable compatibility, outstanding cell adhesion properties, and slow degradation capacity, and the sustained release of Agomir‐29a‐Exos (Exosomes derived from Agomir‐29a transfected BMSCs) from HMPs enhanced the proliferation and migration of BMSCs and HUVECs (Human Umbilical Vein Endothelial Cells) while promoting osteogenesis and angiogenesis. Overall, the findings demonstrate that the HMP@Exo system can effectively maintain the activity and half‐life of Exos, accompanied by overexpression of miR‐29a (microRNA‐29a). The injectable system provides an innovative approach for accelerating fracture healing by coupling osteogenesis and angiogenesis.